D-homophenylalanine, which is represented by the following formula: ##STR1## is an important starting material for anti-hypertensive drugs such as Enalapril, Lisinopril, and Quinapril. It has been reported that the chirality of C.sub.2 is the homophenylalanine moiety of Enalapril is very important to its biological activities of angiotensin-converting enzyme inhibition; change of the chirality from the S(D) to R(L) configuration led to a 7.times.10.sup.2 -fold decrease of the converting enzyme inhibitory activities of Enalapril.
In this endeavor, D-homophenylalanine is first converted to ethyl ester of D-homophenylalanine, which is represented by the following formula: ##STR2##
From the D-homophenylalanine ethyl ester, Enalapril, Lisinopril, and Quinapril are synthesized. These anti-hypertensive drugs are represented by the following formulas: ##STR3##
A very significant potential market is expected for the drugs related to D-homophenylalanine (including the Enalapril, Lisinopril, and Quinapril mentioned above). Therefore, there exists enormous economic incentive for the development of cost-effective processes for the production of optically active D-homophenylalanine.
In Japan Pat. App. JP 86-205850, it is disclosed a method for the preparation of optically active L-homophenylalanine by optical resolution via diastereomeric salts of racemic acetylhomophenylalanine. In JP 86-205850, optically active PhCH2CH2CH(NH2)CO2H is prepared by treatment of N-acetyl-DL-homophenylalanine with optically active PhCHMeNH2 in a solvent to prepare a solution containing two diastereomeric salts, from which a sparingly solution salt is separated, decomposed, and hydrolyzed. One of the disadvantages of the JP 86-205850 is the very high cost involved.
In Japan Pat. App. JP 86-291480, it is disclosed a method for the preparation of optically active D-homophenylalanine by resolution of DL-homophenylalanine, in which D-(-)-Mandelic acid and DL-homophenylalanine were dissolved in an aqueous alcohol solution, then the solution was cooled with crystalline D-(-)-Mandelic acid and L-homophenylalanine salts. The JP 86-291480 process also involves relatively high cost.
Syldatk, C., et al, in an article entitled: "Biotechnological Production of Unnatural L-Amino Acids from D,L-5-Monosubstituted Hydantoins," Biotech. Letters, Vol. 14, No. 2, pp. 105-110 (February 1992), disclosed a method for the bioconversion of D,L-5-.alpha.- and D,L-5-.beta.-naphthylmethylhydantoin to their corresponding L-amino acids using besting cells of Arthrobacter sp. (DSM 3745). Similar techniques were also disclosed in JP 87-279147 and JP 89-97523. JP-89-97523 discloses a method for manufacturing D-homophenylalanine by treating 5-benzylmethylhydantoin with Pseudomonas, Achromobacter, Alcaligenes, Serratia, Aspergillus, Rhizomucor, or D-hydantoin hydrolase from the microorganisms. P. testosteroi ATCC 11996 was cultured in a medium containing glucose, yeast extract, polypeptone, NaCl and 5-benzylmethylhydantoin at 26.degree. C. for 48 hours, then centrifuged. The bacteria was treated with 1% 5-benzylmethylhydantoin in phosphate buffer at 37.degree. C. for 72 hours to produce 96.5 .mu.g optically pure D-homophenylalanine per ml. One of the main disadvantages of the bioconversion processes is that the microorganisms are very process specific, and it often involves a very tedious undertaking to screen and identify all the microorganism candidates that may work.
Tseng, Tsung-Chin, et al, in an article entitled: "Enantioselective Synthesis of N-[(S)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline from Chiral Synthon Prepared Enzymatically; A Practical Method for Large-Scale Synthesis," J. of the Chinese Chem. Soc., vol. 38, pp. 487-490 (1991), disclosed a process for stereospecific synthesis of Enalapril; the starting material, (R)-2-hydroxy-4-phenylbutyronitrile was prepared from lipase-catalyzed acetylation in dichloromethane solvent. This process is very slow; it took twelve days to complete the reaction.
Recently, several studies have demonstrated the possibility of using proteases as catalysts in organic solvents for the resolution of N-protected amino acids. For example, Chen, Shui-Tein, et al, in an article entitled: "Kinetic Resolution of N-Protected Amino Acid Esters in Organic Solvents Catalyzed by a Stable Industrial Alkaline Protease," Biotechnology letters, vol. 13, No. 11, pp. 773-778 (1991), it was disclosed that an industrial alkaline protease "Alcalase" was found to be usable as a catalyst for resolution of N-protected amino acids; only L-amino acid ester has been hydrolyzed. This method requires the extra steps of adding protective groups before the enzymatic reaction, and removing the protective groups after reaction. In another article entitled: "Enzymes in Organic Synthesis: Use of Subtilisin and a Highly Stable Mutant Derived from Multiple Site-Specific Mutations," J. Amer. Chem. Soc., vol. 112, pp. 945-953 (1990), Wong Chi-Huey disclosed the use of subtilisin 8350, a protease, in the enzymatic resolution of non-N-protected DL-amino acid esters by hydrolysis. One of the main disadvantages of this process is that the catalyst subtilisin 8350 causes the final product L-HPA to polymerize and form peptide.
More recently, in an article entitled: "Facile Optical Resolution of Amino Acid Esters Via Hydrolysis by an Industrial Enzyme in Organic Solvents," J. Chem. Tech. Biotechnol. vo. 59, pp. 61-65 (1994), Kijima T., disclosed that racemic amino acid esters can be optically resolved via hydrolysis in organic solvents by catalysis of an industrial alkaline, "Alcalase". In that article, it was found that, above 70% (v/v) water content, the e.e. (enantiometric excess) decreased sharply.